MX2008007437A - Crystalline lestaurtinib hydrates and crystalline lestaurtinib hemihydrate hemiacetonitrileate and crystalline lestaurtinib hemihydrate hemitetrahydrofuranate - Google Patents

Abstract

Crystalline lestaurtinib hydrates and crystalline lestaurtinib hemihydrate hemicetonitrileate and crystalline lestaurtinib hemihydrate hemitetrahydrofuranate, processes to reproducibly make them and methods of treating patients using them are disclosed.

Description

HYDRATES OF LESTAURTINIB CRYSTALINE AND HEMIACETONITRILEATE OF HEMIHYDRATE OF LESTAURTINIB CRYSTALLINE AND HEMITETRAHYDROFURANATE OF HEMIHYDRATE OF LESTAURTINIB CRISTALINO This application claims priority for the United States Provisional Application No. Serial No. 60 / 748,855, filed on December 9, 2005 Field of the Invention The invention relates to crystalline lestaurtmib hydrates and hemiacetonitpleate of crystalline lestaurtinib hemihydrate and crystalline lestaurtmib hemihydrate hemitehydrofuranate processes to effect the reproducibility of these and methods for treating patients using the same BACKGROUND OF THE INVENTION Lestaurtinib is an orally semi-synthetic, bioavailable receptor tyrosma kinase inhibitor that has been shown to have therapeutic utility to treat conditions such as acute myeloid leukemia, chronic myeloid leukemia and acute nymphocytic leukemia. It is a synthetic derivative of K-252- a, a fermentation product of Nonomurea longicatena, and belongs to a class of indolocarbazole alkaloids. U.S. Patent 4,923,986 describes lestaurtmib, also known as (9S-9a, 10β, 12a)) - 2,3,9, 10,11,12-hexahydro-10-hydroxy-10- (hydroxymethyl) -9-methyl-9,12-epoxy-1H-diindole [1,2,3-fg: 3 ', 2', 1'-kl ] pyrrole [3,4-i] [1,6] benzodiazocin-1-one (Cas Registry No. 111358-88-4), and its usefulness. The solvates of Lestaurtinib can have different melting points, solubilities or ranges of solubility, whose physical properties, either alone or in combination, can affect their bioavailability. Due to the knowledge of crystallinity, or high cost thereof, the solvates of lestaurtinib can provide guidance during clinical development, there is an existing need for the identification of different crystalline forms of lestaurtinib solvates, processes to effect their reproducibility and methods for treating them. patients using these.

Brief Description of the Invention One embodiment of this invention, therefore, relates to characterized isolated crystalline lestaurtinib hydrates, when measured at about 25 ° C with Cu-Ka radiation, by a powder diffraction pattern with at least three peaks that have 2T values of approximately 7.1 °, 8.2 °, 10.2 °, 12.9 °, 14.5 °, 14.9 °, 16.4 °, 20.6 °, 25.3 °, 26.1 °, or 26.4 °. Another embodiment refers to crystalline lestaurtinib monohydrate characterized, when measured at about 25 ° C with Mo-Ka radiation, by a powder diffraction pattern with at least three peaks having 2T values of approximately 7.1 °, 82 °, 102 °, 129 °, 145 °, 149 °, 164 °, 206 °, 253 °, 26 °, or 264 ° Another embodiment refers to lestaurtinib monohydrate characterized in the orthorhombic crystal system and space group P212121, when it is measured at approximately 25 ° C with Cu-Ka radiation, by reticular parameters a, b and c of 7101Á, 11 994Á and 25000Á, respectively Another embodiment refers to crystalline lestaurtinib hydrates characterized, when measured at about 25 ° C with Cu-Ka radiation, by a powder diffraction pattern with at least three peaks having 2T values of about 70 °, 140 °, 144 °, 148 °, 156 °, 189 °, 255 °, 265 ° or 355 ° Another embodiment refers to crystalline lestaurtmib tphid time characterized, when measured at about 25 ° C with Cu-Ka radiation, by a dust diffraction pattern with the minus three peaks that have 2T values of approximately 70 °, 14 °, 144 °, 148 °, 156 °, 189 °, 255 °, 265 ° or 355 ° Another modality refers to crystalline lestaurtmib tphidrate characterized in the orthorhombic crystal system and space group P2Í2T2 !, when measured at about -100 C with Mo-Ka radiation, by lattice parameters a, b and c of 70489A ± 00006A, 12720 ± 0001A and 25292A ± 0002A, respectively. Another embodiment refers to compositions comprising or being made from a hydrate of lestaurtmib crystalline, or a mixture thereof, and an excipient Another embodiment refers to a method for treating patients having a condition caused or exacerbated by unregulated or over-expressed tyrosine kinase receptor comprising administering to them a therapeutically acceptable amount of a hydrate of isolated crystalline lestaurtinib, or a mixture thereof. Another embodiment relates to a method of treating patients having acute myeloid leukemia comprising administering to them a therapeutically acceptable amount of a crystalline lestaurtinib hydrate, or a mixture thereof. Another embodiment relates to a method of treating patients having chronic myeloid leukemia comprising administering to them a therapeutically acceptable amount of a crystalline lestaurtinib hydrate, or a mixture thereof. Another embodiment relates to a method for treating patients having acute lymphocytic leukemia comprising administering to them a therapeutically acceptable amount of an isolated crystalline lestaurtinib hydrate, or a mixture thereof. Another embodiment relates to a method of treating patients having chronic lymphocytic leukemia comprising administering to them a therapeutically acceptable amount of an isolated crystalline lestaurtinib hydrate, or a mixture thereof. Another embodiment refers to a process for making crystalline lestaurtinib monohydrate comprising: exposing crystalline lestaurtinib anhydrate or crystalline lestaurtinib trihydrate for relative humidity of between about 10% and 40% and isolating the crystalline lestaurtmib monohydrate. Another embodiment refers to a process for making crystalline lestaurtmib tphidrate comprising exposing crystalline lestaurtmib anhydrate or crystalline lestaurtmib monohydrate for relative humidity greater than 40% and isolating the crystalline lestaurtmib tphidrate Another embodiment refers to crystalline lestaurtinib hemihydrate hemiacetonitpleate characterized, when measured at approximately 25 ° C with Cu-Ka radiation, using a powder diffraction pattern with at least three peaks having 2T values of approximately 77 °, 80 °, 82 °, 98 °, 120 °, 141 °, 146 °, 155 °, 172 °, 179 °, 182 °, 186 °, 198 °, 21 6 °, 223 °, 233 °, 254 ° or 256 ° Another modality refers to The hemiacetonitpleate of crystalline lestaurtmib hemihydrate characterized in the monocyclic crystal system and the P2L space group when measured at approximately -100 ° C with Mo-Ka radiation, by reticular parameters a, b and c of 136358 ± 00001A, 228320A ± 00004A and 158260 ± 00002A, respectively and ß of 113147 ° ± 0001 ° Another embodiment refers to hemitetrahydrofuranate of crystalline lestaurtmib hemihydrate characterized in the monocyclic crystal system and P2L space group when measured at about -100 ° C with Mo-Ka radiation , by means of grid parameters a, b and c of 13541A ± 0004Á, 22756A ± 0008Á and 15935Á ± 0005Á, respectively and ß of 113411 ° ± 0006 ° Another embodiment refers to a process for preparing hemiacetonitpleate of crystalline lestaurtmib hemihydrate comprising providing a mixture of lestaurtmib and acetonitplo in which the lestaurtmib is completely soluble in the acetonitplo cause hemiacetonitpleate of crystalline lestaurtmib hemihydrate to exist in the mixture and isolate the hemiacetonitpleate of crystalline lestaurtinib hemihydrate Another modality refers to a process for making hemiacetonitpleate of crystalline lestaurtmib hemihydrate which comprises providing a mixture comprising lestaurtmib and acetonitplo, in which lestaurtmib is completely soluble in acetonitoplo, causing hemiacetonitpleate of crystalline lestaurtmib hemihydrate to exist in the mixture by adding water to the mixture, and isolating the hemiacetonitpleate of crystalline lestaurtinib hemihydrate. refers to a process for making hemi-tetrahydrofuranate of crystalline lestaurtmib hemihydrate comprising providing a mixture of lestaurtmib and tetrahydrofuran, in which lestaurtmib is completely soluble in tetrahydrofuran; cause hemitetrahydrofuranate of crystalline lestarutinib hemihydrate to exist in the mixture and isolate the hemitetrahydrofuranate from crystalline lestaurtinib hemihydrate. Another embodiment relates to a process for making hemi-tetrahydrofuranate of crystalline lestaurtinib hemihydrate comprising: providing a mixture comprising lestaurtinib and tetrahydrofuran, in which lestaurtinib is completely soluble in tetrahydrofuran; cause hemitetrahydrofuranate of crystalline lestaurtinib hemihydrate to exist in the mixture by adding water to the mixture; and isolating hemitetrahydrofuranate from crystalline lestaurtinib hemihydrate.

Detailed Description of the Invention Crystalline forms different from a given drug have physical, pharmaceutical, physiological and biological properties that can differ markedly from one to another. This invention relates to crystalline forms of lestaurtinib solvates. It is intended that it be understood that the term "isolated lestaurtinib solvate", as used herein, means a particular crystalline lestaurtinib solvate such as, but not limited to, lestaurtinib monohydrate, lestaurtinib trihydrate, hemacetonitrileate of lestaurtinib hemihydrate , hemitetrahydrofuranate of lestaurtinib hemihydrate, mixtures thereof and the like. It is also intended that it be understood that the term "isolated lestarutinib hydrate", as used herein, means a particular crystalline lestaurtinib hydrate such as, but not limited to, lestaurtinib monohydrate, lestarutinib trihydrate, and the like. The crystalline lestarutinib monohydrate is stable to relative RH from about 40% to about 10% at about 25 ° C. At room temperature and above RH of 40%, the monohydrate rapidly converts to trihydrate. When grinded by hand and mortar, the ability to absorb water from the crystalline lestaurtinib monohydrate is reduced by a factor of about 6. In this way it is taken about 6 times more to absorb similar amounts of water when it is ground than when it is not ground. . Lestaurtinib monohydrate can be made by exposing the trihydrate to RH levels of 40% or less at room temperature by heating the trihydrate between 80 ° C and 200 ° C, followed by exposure to ambient conditions for approximately 10 minutes. After the exposure period, the sample must be stored in a sealed container. Crystalline lestaurtinib anhydrate is stable at room temperature between about RH of 0% and about 5%, but absorbs moisture above 5% RH to form crystalline lestaurtmib monohydrate The existence of crystalline lestaurtinib anhydrate was demonstrated by sorption gravimetry of dynamic humidity (DMSG) which showed, at 25 ° C, a solid state phase between RH of 0% and 5% with less than 5% water Because the mediated moisture crystallization was not observed during the RH levels between 5% and 10%, it was concluded that the solid at 5% RH was crystalline, and because the solid contained less than 5% water, it was also determined that it was an anhydrate. The crystalline lestaurtmib anhydrate can be produced by either exposing a crystalline lestaurtmib anhydrate at RH levels of 5% or less at room temperature or by heating the tphidrate between 80 ° C and 200 ° C and storing the product under free conditions The sample can absorb water from the atmosphere during the transfer period The hemiacetonitpleate of crystalline lestaurtmib hemihydrate is a crystalline mixed solvate with approximately 1 mole equivalent of water and approximately Vi mole equivalent of acetonitoplo The solvents are trapped within the glass lattice and can be removed by heating a sample between 130 ° C and 220 ° C. X-ray powder diffraction data were obtained with a model unit X1 Scintag with a copper target (radiation of wavelength 1 54060 A, 45 Kv and 40 ma), scanning speed 1 ° per continuous minute, and a scanning speed of 2-40 ° 20T at room temperature using a Peltier cooled detector for copper radiation All XRPD samples were gently ground to obtain a fine powder by hand and in mortar before analysis The term "amorphous" as used herein means a super-cool liquid or a viscous liquid which looks like a solid but does not have a regularly repeated placement of molecules that is maintained over a range and does not have a melting point but rather softens or softens above its transition temperature. "solvent", as used herein, means a solvent in which a compound is substantially insoluble. The term "crystalline", as used herein, means that it has a regularly repeated placement of molecules or planes of an external face. The term "isolated" as used herein, it means to separate a compound from a solvent, anti-solvent, or a mixture of solvent and anti-solvent to provide a solid, semi-dry or honey. This is typically accompanied by means such as centrifugation, filtration with or without aspiration. , filtration under positive pressure, distillation, evaporation or a combination thereof Isolating may or may not be accompanied by purification during the at which the purity of the chemical, chiral or chemical and chiral of the isolate is increased The purification is typically conducted by means such as crystallization, distillation, extraction filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral, column chromatography on a column packed with a chiral stationary phase, filtration through a porous glass or glass barrier, silica gel column chromatography, ion exchange chromatography, recrystallization, high performance liquid chromatography normal phase, reverse phase high resolution liquid chromatography, grinding and the like The term "miscible" as used herein, means capable of combining without phase separation The term "solvate" as used herein, means that it has on a surface, in a grid or on a surface and in a grid, a solvent such as water, acid acetic, acetone, acetonitoplo, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-d? oxane, ethanol, ethyl acetate, butanol, tert-butanol, N, Nd? met? lacetam? da, N, Nd? met? lformam? da , formamide, formic acid, heptane, hexane, isopropanol, methanol, ethyl methyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, propylene glycol, propanol, 2-propanone, pipdin, tetrahydrofuran, toluene, xylene, mixtures thereof and the like A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or on the surface and in the lattice, is water. Hydrates may or may not have other solvents other than water on the surface, in the grid or on the surface and in the reticle of the substance The term "solvent", as used herein, means a substance, typically a liquid, that is capable of partially or completely dissolving another substance, typically a solid The solvents for the practice of this invention include water, ac Ethical, acetone, acetonitoplo, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-d? oxane, ethanol, ethyl acetate, butanol, tert-butanol, N, Nd? met? lacetam? da, N, Nd? Met? Lformam? Da, formamide, formic acid, heptane, hexane, isopropanol, methanol, ethyl methyl ketone, 1-met? L-2-p? Rrol? D? Nona, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pipdin, tetrahydrofuran, toluene, xylene, mixtures thereof and the like The term "supersaturated" as used herein, means having a compound in a solvent in which it is completely dissolved at a certain temperature but at which the solubility of the compound in the solvent at that certain temperature is exceeded Unless stated otherwise, the percentages established through this specification are percentages of weight / weight (w / w) The mixtures comprising lestaurtmib and solvent may or may not have Diastereopropic and chemical impurities, which, if present Thus, they can be completely soluble, partially soluble or essentially insoluble in the solvent. The level of diastereomeric or chemical impurities in the mixture can be lower before or during the crystalline form isolation of Lestaurtmib by means such as distillation, extraction, filtration through Acidic, basic or neutral alumina, filtration through acidic, basic or neutral charcoal, column chromatography on a packed column with a chiral stationary phase, filtration through a barrier of porous, plastic or glass paper, column chromatography on silica gel, ion exchange chromatography, recrystallization, normal phase high resolution liquid chromatography, reverse phase high performance liquid chromatography, grinding and the like Lestaurtmib and solvent mixtures, where lestaurtmib is completely dissolved in the solvent can be prepared from a lestaurtmib cri stalino, amorphous lestaurtmib, a lestaurtinib solvate or a mixture thereof is intended to be understood that, because several solvents and anti-solvents contain impurities, the level of impurities in the solvents and anti-solvents for the The practice of this invention, if present, is at sufficiently low concentration so that it does not interfere with the intended use of the solvent when the impurities are present. The solvents used were HPLC, reagent or USP grade and were used as received. The invention provides methods for treating conditions and conditions in a patient comprising administering to them a therapeutically acceptable amount of lestaurtmib. Therefore, lestaurtinib is useful for treating a variety of therapeutic indications. For example, lestaurtmib is useful for treatment of cancers such as carcinomas of the pancreas, prostate, breast, thyroid, colon and lung, malignant melanomas ignos, glioblastomas; Derived neuroectodermal tumors including Wilm's tumor, neuroblastomas and medulloblastomas; and leukemias such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL); pathological conditions of the prostate such as prostate cancer or hypertrophy; carcinomas of the pancreas, such as pancreatic ductal adenocarcinoma (PDAC); hyperproliferative disorders such as proliferative skin disorders including actinic keratosis, basal cell carcinoma, squamous cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberances, hamangioma, wine stain, xanthoma, Kaposi's sarcoma, mastocytosis, mycosis fungoides, lentigo, nevocellular nevus , malignant lentigo, malignant melanoma, metastatic carcinoma, and various forms of psoriasis, including psoriasis vulgaris and psoriasis eosinophilia; and myeloproliferative disorders and related disorders associated with JAK2 activation and myeloproliferative disorders and related disorders including, but not limited to, myeloproliferative disorders such as, for example, polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM) ), also called chronic idiopathic myelofibrosis (CIMF), unclassified myeloproliferative disorders (uMPDs), hypereosinophilic syndrome (HES), and systemic mastocytosis (SM). Lestarutinib hydrates can be administered by any means resulting in contact of the active agent with the site of the agent of action in the body of the patient Lestaurtmib hydrates can be administered by any conventional means, either as an individual therapeutic agent or in combination with other therapeutic agents Lestaurtmib hydrates are preferably administered to patients in need of them in therapeutically effective amounts for the treatment of the conditions and disorders described herein. Therapeutically effective amounts of a lestarutinib hydrate can be rapidly determined by a diagnosis of care by the use of conventional techniques The effective dose may vary depending on a number of factors, including type and extent of the progression of the disorder or disorder, especially the health of a particular patient, the biological efficacy of the lestau rtmib, lestaurtmib hydrate formulation, and route of administration of lestaurtinib hydrate forms Lestaurtmib hydrates can also be administered at lower dosage levels with gradual increase until the desired effect is obtained. As used herein, the term "approximately", refers to a range of values of ± 10% of a specified value For example, the phrase "approximately 50 mg" includes ± 10% of 50 or from 45 to 55 mg Typical dose ranges of hydrates of lestaurtmib comprise from about 001 mg / kg to about 100 mg / kg of body weight per day or from about 001 mg / kg to 10 mg / kg of body weight per day Daily doses for human adults include approximately 20, 25 30, 35 , 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 120, 140, 160 and 200 mg and an equivalent dose for a human child Lestaurtinib hydrates can be administered in one or more dosage unit forms and they can also be administered one to four times a day, including twice daily (BID). Lestaurtmib unit dose ranges comprise from about 1 to about 400 mg given one to four times a day, or from about 10 mg to about 200 mg BID, or 20-80 mg BID, or 60-100 mg BID or approximately 40, 60, 80 or 100 mg BID Dosage of hydrate forms of lestaurtmib can also be in the form of liquids or suspensions in a concentration between 15 to 25 mg / mL, 16 mg / mL or 25 mg / mL The liquid or suspension dosage forms of lestaurtinib hydrates may include the equivalent of the doses (mg) described above For example, dosages of lestarutinib hydrates can include 1 to 5 mL of the 25 mg / mL solution, or 1, 1 2, 1 4, 1 6, 1 8, 2, 22, 24, 26, 28, 3, 32 , 34, 36, 38, or 4 mL of the 25 mg / mL solution, wherein a 60 mg dose of a lestaurtmib hydrate can be provided in 24 mL of solution, a dose of 80 mg of a lestaurtinib hydrate can be provided in 32 mL of solution and a dose of 100 mg of lestaurtinib hydrate can be provided in 4 mL of solution Additionally, a dose of 20 mg of a lestaurtmib hydrate can be provided with 1 25 mL of a solution of 16 mg / mL The daily dose of a lestarutinib hydrate can range from 1 mg to 5 mg / kg (normalization based on an average body weight of about 65 kg) For example, a daily dose of a form of a lestaurtinib hydrate is about 1 to 3 mg / kg or about 1 2 to 25 mg / kg, or about 1 2, 1 4, 1 6, 1 8, 2, 22, 24, 26, 28, or 3 mg / kg In One me all alternative to describing an effective dose, an oral unit dose of a lestaurtinib hydrate is one that is necessary to obtain a serum level in the blood of about 005 to 20 μg / mL or 1 to 20 μg / mL in a Patient Lestaurtinib hydrates can be formulated into pharmaceutical compositions by mixing the forms with one or more pharmaceutically acceptable excipients. It is intended that it be understood that the pharmaceutical compositions include any form of a lestarutinib hydrate or any combination thereof. pharmaceutically acceptable excipients "as used herein, includes any and all solvents, dispersion media, coatings, antifungal and antibacterial agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known. in art, such as in Remmgton The Science and Practice of Pharmacy, 20th ed, Gennaro, A R, Ed, Lippincott Williams &; Wilkms Philadelphia, PA, 2000 Except where conventional means or agent is compatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplemental active ingredients may also be incorporated into the compositions. The excipients for the preparation of compositions comprising Hydrates of lestaurtinib to be administered orally include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butyl glycol, carbomers, castor oil, cellulose, cellulose acetate, butter cocoa, corn starch, corn oil, cottonseed oil, povidone cross, dig ceptus, ethanol, ethyl cellulose, lime laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, g cerol, ground walnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, man itol, monoglycepdos, olive oil, peanut oil, potassium phosphate salts, potato starches, povidone, propylene glycol, Ringer's solution, sunflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts , sodium laupl sulfate, sodium sorbitol, soybean oil, stearic acids, stearate fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfupl alcohol, tpglicépdos, water and mixtures thereof The excipients for the preparation of compositions comprising forms of hydrates of lestaurtmib to be administered either optically or orally include, for example, 1,3-butyl glycol, castor oil, corn oil, cottonseed oil, ethanol, sorbitan fatty acid esters, germ oil, milled walnut oil, g cerol, isopropanol, olive oil, pohetilen g cabbages, propylene glycol, sesame oil, water mixtures thereof Excipients for the preparation of compositions c They comprise lestaurtmib hydrates to be osmotically administered include, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof. The excipients for the preparation of compositions comprising forms of hydrates of lestaurtmib to be administered parenterally include, for example, 1 3-butaned? Ol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, ground nut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, oil sunflower, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water and mixtures thereof Excipients for the preparation of compositions comprising forms of hydrates of lestaurtmib to be administered rectally or vaginally include, for example, butter of cocoa, polyethylene glycol, wax and mixtures thereof The dosage forms of the hydrates of lestaurtmib and compositions which They learn lestaurtmib hydrates depend on the route of administration Any route of administration is contemplated, including oral, mucosal (eg ocular, intranasal, pulmonary, intestinal, rectal, vaginal and urethral) or parenteral (eg subcutaneous, intradermal, intramuscular, intravenous or intrapeptoneal) The pharmaceutical compositions are more preferably administered orally preferably in forms such as tablets, capsules, powders, pills, liquids / suspensions or gels / suspensions, or emulsions, lyophilized and all other forms described in patents and applications mentioned herein , more preferably as tablets, capsules and liquids / suspensions or gels / suspensions. The administration vehicle may comprise one or more pharmaceutically acceptable carriers that are similar to ensure the solid state or stability of crystalline form (eg suspension in oil). lestaurtinib can be formulated as a variety of pharmaceutical compositions and dosage forms, such as those described in U.S. Patents 6,200,968 and 6,660,729 and PCT Publication No. 04/037928, each of which is incorporated herein by reference. In particular, lestaurtinib can be formulated as microemulsions or dispersions. In some embodiments, the compositions comprise a hydrate of lestaurtinib, propylene g, and a polyoxyethylene sorbitan fatty acid ester, examples which include TWEEN® 20 (oxyethylene po sorbitan monolaurate 20), TWEEN® 40 (polyoxyethylene sorbitan monopalmitate 20), and TWEEN® 80 (monoolateria po oxyethylene 20 sorbitan) In a particular embodiment, lestaurtmib hydrate is present at a concentration of 25 mg / mL. In another embodiment, the ratio of propylene ghcol to the ester of the fatty acid ester oxyethylene sorbitan has a range of 5050 to 8020 or 5050 or 8020 In other embodiments, the compositions comprise a lestaurtmib hydrate, a polyoxyl stearate and polyethylene glycol ("PEG"), examples which include PEG 300-8000, 400-3350 or 400-1500 Daltons or PEG-400, PEG-600, PEG-1000, PEG-1450, PEG-1500, PEG-400 / PEG -1000, PEG-400 / PEG-1450, PEG-600 / PEG-1000 or PEG-600 / PEG-1450 In other embodiments, polyoxyl stearate is polyoxyl 40 stearate (MYRJ 52®) In particular embodiments the hydrate of lestaurtmib is present at a concentration of 25 mg / mL. In other embodiments, the ratio of polyethylene glycol to pohoxil stearate has a range of 5050 to 8020 or proportions of 5050 or 8020. In some embodiments, the compositions comprise PEG- 400, PEG-1000 and pohoxyl stearate in a proportion of 252550 or PEG-400, PEG-1450 and pohoxyl estereate in a proportion of 252550 or PEG-600, PEG 1000 and polyoxyl stearate in a proportion of 252550 or PEG- 600 PEG-1450 polyoxyl stearate in a proportion of 252550 In other embodiments, the composition comprises PEG-400, PEG-1000, and polyoxyl stearate in a proportion of 404020 or PEG-400, PEG-1450 and pohoxyl stearate in a proportion of 404020 or PEG-600, PEG-1000 and polyoxyl stearate in a ratio of 404020 or PEG 600, PEG-1450 and polyoxyl stearate in a 404020 ratio In another embodiment of this invention, the composition includes an antioxidant therein. The term "antioxidant" as used herein, refers to a substance that retards determing by oxidation or inhibits reactions promoted by oxygen or peroxides. Antioxidants include , but are not limited to ascorbic acid, fatty acid esters or ascorbic acid, butylated hydroxytoluene (BHT), propyl gallate, butylated hydroxyanisole, mixtures thereof and the like In some embodiments of this invention, microemulsions or solid solution compositions which they comprise lestaurtmib also comprise BHT, and in particular BHT 002% p / p Lestaurtmib hydrates can be made by chemical processes without The above is intended to be understood that the order of the steps in the processes may vary, that the reactants, solvents and reaction conditions may be replaced by those specifically mentioned, and that the portions susceptible to unwanted reactions can be protected and unprotected, as necessary The following examples are presented to provide what is considered to be the most easily understandable and useful description of the procedures and conceptual aspects of this invention Preparative Example 1 The lestaurtinib and the methanolate thereof was prepared as described in U.S. Patent No. 4,932,986 Example 1 Form 1 Crystalline Lestaurtinib A mixture of lestarutinib methanolate in methanol and acetone was filtered for cleaning. The filtrate was distilled at constant volume with the addition of isopropyl acetate. When the boiling point of the solvent was stabilized at 82 ° C, the mixture was cooled and cast Example 2 Lestaurtinib Hydrated Crystalline A mixture of lestaurtinib (400 mg) in refluxing acetone (200 mL), in which lestaurtmib was completely soluble, was treated with water until turbid, cooled, stored in the dark at room temperature for 3 hours. days and filtered through an agglomerated glass funnel of medium porosity. The filtrate was washed with water and dried with air. Exposure of the product at relative humidity less than 40% provided crystalline lestaurtmib monohydrate. Exposure of the product at a relative humidity of 40% or more provided tphid crystalline lestaurtmib time Example 2A Crystalline Hydrated Lestaurtmib A mixture of lestaurtmib (1 2 g) at reflux 1,3-d-oxolane, in which lestaurtinib was completely soluble (120 mL), was poured into water (600 mL), stored in the dark at room temperature for 6 days and filtered through an agglomerated glass funnel of medium porosity. The filtrate was washed with water (10 mL) and air dried. Exposure of the product at relative humidity less than 40% provided crystalline lestaurtinib monohydrate. Exposure of the product to relative humidity of 40% or more provided crystalline lestaurtmib tphidrate Example 3 Hemiacetonitpleate of Crystalline Lestaurtmib Hemihydrate A solution of lestaurtmib (300 mg) in refluxing acetonite (150 mL), in which lestaurtmib was completely soluble, was treated with water until turbid, cooled, stored in the dark at room temperature environment for 24 hours and filtered Example 4 Amorphous Lestaurtmib A mixture of lestaurtinib (16 g) in isopropanol (350 mL) and 1,3-d-oxolane (50 mL) at 80 ° C and in which the lestaurtmib was completely soluble, was concentrated under aspiration. concentrate was washed with isopropanol (10 mL) and air dried Example 4A Amorphous Lestaurtinib A mixture of lestaurtinib (1.1 g) in acetone (250 mL), in which lestaurtinib was completely soluble, was concentrated at 65 ° C under suction. The concentrate was washed with isopropanol (10 mL) and air dried. Additional modes for preparing amorphous lestaurtinib were shown in Table 1. The concentrations were carried out at about the temperature indicated in Table 1 at about 0.5 atm.

TABLE 1 Example 5 Crystalline Lestaurtinib Anhydrate Hydrated crystalline lestaurtinib was heated between about 80 ° C and 100 ° C at about 760 mm Hg (1 atm) pressure. The product was stored in an environment having less than approximately 5% relative humidity.

Example 6 Form 1 Crystalline Lestaurtinib A mixture of EXAMPLE 2, EXAMPLE 2A, EXAMPLE 4, EXAMPLE 4A or a mixture thereof in ethanol, in which the example, or the mixture thereof, was partially soluble, was allowed to chain, with or without stirring, until the crystalline form 1 of Lestaurtmib was formed Example 7 Crystalline Lestaurtinib Hemihydrate Hemihydrate In a refluxing solution of lestaurtmib in THF, in which lestaurtinib was completely soluble, it was treated with water until turbid, cooled, stored in the dark at room temperature for 24 hours and filtered. It is intended that it be understood that peak heights in a PXRD spectrum may vary and will depend on variables such as temperature, size of crystal size or morphology, sample preparation, or sample height in the analysis well of the Standard System. Diffraction Sc? ntagx2 It is also intended to be understood that peak positions can vary when measured with different radiation sources. For example Cu-Ka radiationMo-Ka, Co-Ka and Fe-Ka, which have wavelengths of 1 54060Á, 07107 A, 1 7902 A and 1 9373 A, respectively, can provide peak positions that differ from those measured with Cu- radiation. Ka The term "approximately" that precedes a series of peak positions means that it includes all the peak positions of the group to which it precedes The term "approximately" that precedes a series of peak positions means that all peaks of the group to which it precedes are reported in terms of angular positions with a variable of ± 01 ° For example, the phrase approximately 70 °, 140 °, 144 °, 148 °, 156 °, 189 °, 255 °, 265 ° or 355 ° means approximately 70 ° approximately 140 °, approximately 144 °, approximately 148 °, approximately 156 °, approximately 189 °, approximately 255 °, approximately 265 ° or approximately 355 ° and also 70 ° ± 01 °, 140 ° ± 01 °, 144 ° ± 01 °, 148 ° ± 0 1 °, 156 ° ± 01 °, 189 ° ± 0 1 °, 2 55 ° ± 0 1 °, 265 ° ± 01 ° or 355 ° ± 01 ° As those skilled in the art will appreciate, numerous modifications and variations of the invention are possible in view of the above teachings It is therefore understood that within the field of the appended claims, the invention can be practiced in other ways than those specifically described herein, and the field of the invention is intended to include all of these variations

Claims (1)

1. CLAIMS 1 An isolated crystalline lestaurtinib hydrate characterized, when measured at about 25 ° C with Cu-Ka radiation, by a powder diffraction pattern with at least three peaks having respective 2T values of approximately 71 °, 82 °, 102 ° , 129 °, 145 °, 149 °, 164 °, 206 °, 253 °, 261 °, or 264 ° 2 The crystalline lestaurtmib monohydrate characterized, when measured at about 25 ° C with Cu-Ka radiation, by a standard powder diffraction with at least three peaks having respective 2T values of approximately 71 °, 82 °, 102 °, 129 °, 145 °, 149 °, 164 °, 206 °, 253 °, 261 °, or 264 ° 3 The crystalline lestaurtinib tphidrate characterized, when measured at about 25 ° C with Cu-Ka radiation, by a powder diffraction pattern with at least three peaks having respective 2T values of approximately 70 °, 140 ° 144 °, 148 ° , 156 °, 189 °, 255 °, 265 ° or 355 ° 4 Crystalline lestaurtinib tphidrate bristling in the orthorhombic crystal system and space group P2, 2.2 !, when measured at approximately -100 ° C with Mo-Ka radiation, by reticular parameters a, b and c of 70489A ± 00006Á, 12720 ± 0001A and 25292A ± 0002A, respectively A method for treating a patient having acute myeloid leukemia comprising administering to the latter a therapeutically acceptable amount of an isolated crystalline lestaurtmib hydrate 6 A method of treating a patient having acute hnfocytic leukemia comprising administering to it an amount Therapeutically acceptable of an isolated crystalline lestaurtmib hydrate 7 A method for treating a patient having chronic lymphocytic leukemia comprising administering to it a therapeutically acceptable amount of an isolated crystalline lestaurtinib hydrate 8 A process for making crystalline lestaurtmib monohydrate comprising exposing anhydrate of crystalline lestaurtinib or tphidrato de lestaur crystalline tin at relative humidity of between about 10% and 40% and isolating the crystalline lestaurtmib monohydrate 9 A process for making crystalline lestaurtinib tphidrate comprising exposing crystalline lestaurtmib anhydrate or crystalline lestaurtinib monohydrate to moisture greater than 40% and isolating the crystalline lestaurtmib tphidrate